OXIME DERIVATIVES

Abstract: The invention concerns oxime derivatives of formula (I) wherein R<4> includes hydrogen, carboxy, carbamoyl and (1-4C)alkyl; R<5> includes hydrogen, (1-4C)alkyl, (3-4C)alkenyl, (3-4C)alkynyl, (2-5C)alkanoyl and cyano-(1-4C)alkyl; Ar<1> is optionally-substituted phenylene or a heteroaryl diradical; A<1> is a direct link to X<1>, or A<1> is (1-4C)alkylene; X<1> is oxy, thio, sulphinyl or sulphonyl; Ar<2> includes optionally-substituted phenylene and thiophenediyl; R<1> is hydrogen, (2-5C)alkanoyl or benzoyl; and R<2> and R<3> together form a group of the formula -A<2>-X<2>-A<3>- which together with the carbon atom to which A<2> and A<3> are attached define a ring having 5 or 6 ring atoms, each of A<2> and A<3> is (1-3C)alkylene and X<2> includes oxy; or a pharmaceutically-acceptable salt thereof; processes for their manufacture; pharmaceutical compositions containing them and their use as 5-lipoxygenase inhibitors.

Description: OXIME DERIVATIVES This invention concerns oxime derivatives and more particularly oxime derivatives which are inhibitors of the enzyme 5-lipoxygenase (hereinafter referred to as 5-LO). The invention also concerns processes for the manufacture of said oxime derivatives and novel pharmaceutical compositions containing them. Also included in the invention is the use of said oxime derivatives in the treatment of various inflammatory and/or allergic diseases in which the direct or indirect products of 5-LO catalysed oxidation of arachidonic acid are involved, and the production of new medicaments for such use. As stated above the oxime derivatives described hereinafter are inhibitors of 5- O, which enzyme is known to be involved in catalysing the oxidation of arachidonic acid to give rise via a cascade process to the physiologically active leukotrienes such as leukotriene B, ( TB.) and the peptido-lipid leukotrienes such as leukotriene C, ( TC.) and leukotriene D, (LTD, ) and various metabolites. The biosynthetic relationship and physiological properties of the leukotrienes are summarised by G.U. Taylor and S.R. Clarke in Trends in Pharmacological Sciences, 1986, _ 1 , 100-103. The leukotrienes and their metabolites have been implicated in the production and development of various inflammatory and allergic diseases such as inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), skin disease (especially psoriasis, eczema and dermatitis) and respiratory disease (especially asthma, bronchitis and allergic rhinitis), and in the production and development of various cardiovascular and cerebrovascular disorders such as myocardial infarction, angina and peripheral vascular disease. In addition the leukotrienes are mediators of inflammatory diseases by virtue of their ability to modulate lymphocyte and leukocyte function. Other physiologically active metabolites of arachidonic acid, such as the prostaglandins and thromboxanes, arise via the action of the enzyme cyclooxygenase on arachidonic acid. It is disclosed in European Patent Application Nos. 0375404 A2 and 0385662 A2 that certain heterocyclic derivatives possess inhibitory properties against 5-LO. Furthermore European Patent Applications Nos. 0409413 and 0420511 are also concerned with heterocyclic derivatives which possess inhibitory properties against 5-LO. We have now discovered that certain oxime derivatives which possess some structural features which are similar to those of the compounds disclosed in the above-mentioned applications but which possess other structural features, in particular oxime groups, which were not envisaged in those earlier applications are effective inhibitors of the enzyme 5-L0 and thus of leukotriene biosyntheses. Thus such compounds are of value as therapeutic agents in the treatment of, for example, allergic conditions, psoriasis, asthma, cardiovascular and cerebrovascular disorders, and/or inflammatory and arthritic conditions, mediated alone or in part by one or more leukotrienes. According to the invention there is provided an oxime derivative of the formula I OR 1 I R 5 0-N=C(R )-Ar 1 -A 1 -X 1 -Ar 2 -C-R 2 I I R 3 wherein R is hydrogen, carboxy, carba oyl, amino, cyano, trifluoromethyl, (l-4C)alkylamino, di-(l-4C)alkylamino, (l-4C)alkyl, (2-5C)alkanoyl, (l-4C)alkoxycarbonyl, N-(l-4C)alkylcarbamoyl, N,N-di-(l-4C)alkylcarbamoyl, (l-4C)alkylthio, (l-4C)alkylsulphinyl, (l-4C)alkylsulphonyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, (l-4C)alkylthio-(l-4C)alkyl, phenyl or phenyl-(l-4C)alkyl and wherein each phenyl group may optionally bear one or two substituents selected from hydroxy, amino, halogeno, cyano, trifluoromethyl, (l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkylamino, di-(l-4C)alkylamino, (l-4C)alkylthio, (l-4C)alkylsulphinyl and (l-4C)alkylsulphonyl; R 5 is hydrogen, (l-4C)alkyl, (3-4C)alkenyl, (3-4C)alkynyl, (2-5C)alkanoyl, halogeno-(2-4C)alkyl, hydroxy-(2-4C)alkyl, (l-4C)alkoxy-(2-4C)alkyl, carbamoyl, N-(l-4C)alkylcarbamoyl, N,N-di-(l-4C)alkylcarbamoyl, cyano-(l-4C)alkyl, carboxy-(l-4C)alkyl, (l-4C)alkoxycarbonyl-(l-4C)alkyl, (2-5C)alkanoyl-(l-4C)alkyl, phenyl-(l-4C)alkyl or heteroaryl-(l-4C)alkyl and wherein each phenyl or heteroaryl group may optionally bear one or two substituents selected from halogeno, cyano, trifluoromethyl, carboxy, (l-4C)alkyl, (l-4C)alkoxy and (l-4C)alkoxycarbonyl; Ar is phenylene or a heteroaryl diradical which may optionally bear one or two substituents selected from halogeno, cyano, trifluoromethyl, hydroxy, amino, (l-4C)alkyl, (l-4C)alkoxy, phenyl-(l-4C)alkoxy, (l-4C)alkylamino and di-(l-4C)alkylamino; 4 1 4 or R is linked to Ar ortho to the -N=C(R )- group and defines an ethylene, propylene, 1-methylpropylene or vinylene group, a group of the formula -CH=CH-X 3 - 3 wherein X is oxy or thio, or a group of the formula "(CH 2 ) n -X 3 - 3 wherein n is 1 or 2, X is oxy, thio, sulphinyl, sulphonyl, imino or (l-4C)alkylimino, and one of the -CH„- groups may optionally be replaced by a -CH(Me)- or -C(He)„- group; 1 1 1 A is a direct link to X , or A is (l-4C)alkylene; X is oxy, thio, sulphinyl or sulphonyl; 2 Ar is phenylene, pyridinediyl, pyrimidinediyl, thiophenediyl, furandiyl, thiazolediyl, oxazolediyl, thiadiazolediyl or oxadiazolediyl which may optionally bear one or two substituents selected from halogeno, cyano, trifluoromethyl, hydroxy, amino, (l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkylamino and di-(l-4C)alkylamino; R is hydrogen, (2-5C)alkanoyl or benzoyl, and wherein said benzoyl group may optionally bear one or two substituents selected from halogeno, (l-4C)alkyl and (l-4C)alkoxy; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 ring having 5 or 6 ring atoms, wherein each of A and A is 2 independently (l-3C)alkylene and X is oxy, thio, sulphinyl, sulphonyl or imino, and which ring may optionally bear one or two substituents selected from hydroxy, (l-4C)alkyl and (l-4C)alkoxy; or a pharmaceutically-acceptable salt thereof. In this specification the generic term "alkyl" includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as "propyl" are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as "isopropyl" are specific for the branched-chain version only. An analogous convention applies to other generic terms. It is to be understood that, insofar as certain of the compounds of the formula I defined above may exhibit the phenomenon of tautomerism and any formula drawing presented herein may represent only one of "the possible tautomeric forms, the invention includes in its definition any tautomeric form of a compound of the formula I which possesses the property of inhibiting 5-LO and is not to be limited merely to any one tautomeric form utilised within the formulae drawings. It is further to be understood that, insofar as it is well known that oxime derivatives may exist in different geometric isomeric forms, commonly designated as (E) - or (^)-isomers, the invention includes in its definition any such geometric isomeric form which possesses the property of inhibiting 5-L0. The separation of such geometric isomeric forms may be possible by the standard laboratory techniques of organic chemistry such as by chromatographic separation of a mixture of said isomeric forms or by crystallisation of one such isomeric form from a mixture thereof. Examples of such techniques are set out in the accompanying Examples which are set out hereinafter. It is further to be understood that, insofar as certain of the compounds of formula I defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the property of inhibiting 5-LO. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Suitable values for the generic terms referred to above include those set out below. 4 5 A suitable value for R or R when it is (1-4C)alkyl, or for 3 the (1-4C)alkyl group when X is (l-4C)alkylimino, is, for example, methyl, ethyl, propyl, isopropyl or butyl; when R or R is (2-5C)alkanoyl is, for example, acetyl, propionyl, butyryl or 4 5 pivaloyl; and when R or R is phenyl-(1-4C)alkyl is, for example, benzyl, phenethyl or 3-phenylpropyl. A suitable value for R when it is (l-4C)alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or tert-butoxycarbonyl; when it is N-(l-4C)alkylcarbamoyl is, for example, N-methylcarbamoyl, N-ethylcarbamoyl or N-propylcarbamoyl; and when it is N_-,N-di-(l-4C)alkylcarbamoyl is, for example, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl or N,N-dipropylcarbamoyl. 4 ' A suitable value for R when it is (l-4C)alkylamino is, for example, methylamino, ethylamino, propylamino or isopropyla ino; when it is di-(l-4C)alkylamino is, for example, dimethylamino, diethylamino or N-ethyl-N-methylamino; when it is (l-4C)alkylthio is, for example, methylthio, ethylthio or propylthio; when it is (l-4C)alkylsulphinyl is, for example, methylsulphinyl, ethylsulphinyl or propylsulphinyl; when it is (l-4C)alkylsulphonyl is, for example, methylsulphonyl, ethylsulphonyl or propylsulphonyl; when it is hydroxy-(1-4C)alkyl is, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl or 3-hydroxypropyl; when it is (l-4C)alkoxy-(l-4C)alkyl is, for example, methoxymethyl, ethoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl; and when it is (1-4C)alkylthio-(1-4C)alkyl is, for example, methylthiomethyl, ethylthiomethyl, 1-methylthioethyl or 2-methylthioethyl. A suitable value for the heteroaryl group in R when R is heteroaryl-(1-4C)alkyl is, for example, a 5-membered or 6-membered heterocyclic moiety containing up to four nitrogen heteroatoms and optionally containing a further heteroatom selected from oxygen and sulphur such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl which may be attached through any available position including through any available nitrogen atom. A suitable value for the (1-4C)alkyl group when R is heteroaryl-(1-4C)alkyl is, for example, methyl, ethyl, propyl, isopropyl or butyl. A convenient value for the heteroaryl group in R when R is heteroaryl-(1-4C)alkyl is, for example, a 5-membered heterocyclic moiety containing up to four nitrogen heteroatoms and optionally containing a further heteroatom selected from oxygen and sulphur such as imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl or tetrazolyl. A further convenient value for the heteroaryl group in R when R is heteroaryl-(1-4C)alkyl is, for example, a 6-membered heterocyclic moiety containing 1 or 2 nitrogen heteroatoms such as pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl. Suitable values for substituents which may be present when 4 5 R or R is phenyl, phenyl-(1-4C)alkyl or heteroaryl-(1-4C)alkyl, or 1 2 for substituents on Ar or Ar , or for substituents on the phenyl group when R is benzoyl, include, for example:- for halogeno: fluoro, chloro and bromo; for (l-4C)alkyl: methyl, ethyl, propyl and isopropyl; for (l-4C)alkoxy: methoxy, ethoxy, propoxy and isopropoxy; for (l-4C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; for (l-4C)alkylamino: methylamino, ethylamino and propylamino; for di-(l-4C)alkylamino: dimethylamino, diethylamino and N-ethyl-N-methylamino; for (l-4C)alkylthio: methylthio, ethylthio and propylthio; for (l-4C)alkylsulphinyl: methylsulphinyl, ethylsulphinyl and propylsulphinyl; for (l-4C)alkylsulphonyl: methylsulphonyl, ethylsulphonyl and propylsulphonyl; for phenyl-(l-4C)alkoxy: benzyloxy and 2-phenylethoxy. A suitable value for R when it is (3-4C)alkenyl is, for example, allyl, 2-butenyl or 3-butenyl; when it is (3-4C)alkynyl is, for example, 2-propynyl or 2-butynyl; when it is halogeno-(2-4C)alkyl is, for example, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 3-fluoropropyl or 3-chloropropyl; when it is hydroxy-(2-4C)alkyl is, for example, 2-hydroxyethyl or 3-hydroxypropyl; when it is (l-4C)alkoxy-(2-4C)alkyl is, for example, 2-methoxyethyl, 2-ethoxyethyl or 3-methoxypropyl; when it is N-(l-4C)alkylcarbamoyl is, for example, N-methylcarbamoyl or N-ethylcarbamoyl; when it is N,N-di-(l-40)alkylcarbamoyl is, for example, N,N-dimethylcarbamoyl or N,N-diethylcarbamoyl; when it is cyano-(1-4C)alkyl is, for example, cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 2-cyanoprop-2-yl or 3-cyanopropyl; when it carboxy-(l-4C)alkyl is, for example, carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 2-carboxyprop-2-yl or 3-carboxypropyl; when it is (l-4C)alkoxycarbonyl-(l-4C)alkyl is, for example, methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, tert-butoxycarbonylmethyl, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-methoxycarbonylprop-2-yl, 2-ethoxycarbonylprop-2-yl, 3-methoxycarbonylpropyl or 3-ethoxycarbonylpropyl; and when it is (2-5C)alkanoyl-(l-4C)alkyl is, for example, acetonyl, propionylmethyl, 1-acetylethyl, 2-acetylethyl or 2-propionylethyl. 1 2 A suitable value for Ar or Ar when it is phenylene is, for example, 1,3- or 1,4-phenylene. A suitable value for Ar when it is a heteroaryl diradical is, for example, a 5-membered or 6-membered heteroaryl diradical containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from oxygen and sulphur such as 2,4-, 2,5- or 3,5-pyridinediyl, 2,5- or 4,6-pyrimidinediyl, 2,5- or 2,6-pyrazinediyl, 3,5- or 3,6-pyridazinediyl, 2,4- or 2,5-imidazolediyl, 2,4- or 2,5-oxazolediyl, 2,4- or 2,5-thiazolediyl, l,2,4-triazole-3,5-diyl, 2,5-oxadiazolediyl or 2,5-thiadiazolediyl. A suitable value for A when it is (l-4C)alkylene is, for example, methylene, ethylene or trimethylene. 2 A suitable value for Ar when it is pyridinediyl, pyrimidinediyl, thiophenediyl, furandiyl, thiazolediyl, oxazolediyl, thiadiazolediyl or oxadiazolediyl is, for example, 2,4-, 2,5- or 3,5-pyridinediyl, 4,6-pyrimidinediyl, 2,4- or 2,5-thiophenediyl, 2,4- or 2,5-furandiyl, 2,4- or 2,5-thiazolediyl, 2,4- or 2,5-oxazolediyl, 2,5-thiadiazolediyl or 2,5-oxadiazolediyl. A suitable value for R when it is (2-5C)alkanoyl is, for example, acetyl, propionyl or butyryl. 2 3 When R and R together form a group of the formula 2 2 3 2 3 -A -X -A - which together with the carbon atom to which A and A are attached define a ring having 5 or 6 ring atoms then a suitable value 2 3 for A or A , which may be the same or different, when each is (l-3C)alkylene is, for example, methylene, ethylene or trimethylene. Suitable values for the substituents which may be present on said 5- or 6-membered ring include, for example:- for (l-4C)alkyl: methyl, ethyl, propyl, isopropyl, butyl and isobutyl; for (l-4C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy. Said substituents may be located on any available position including, when the substituent is (l-4C)alkyl, on the nitrogen atom when -XXI i .s imino. A suitable pharmaceutically-acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition a suitable pharmaceutically-acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. Particular compounds of the invention include, for example, oxime derivatives of the formula I, or pharmaceutically-acceptable salts thereof, wherein:- 4 (a) R is hydrogen, cyano, trifluoromethyl, di-(l-4C)alkylamino, (l-4C)alkyl, (2-5C)alkanoyl, (l-4C)alkoxycarbonyl, (l-4C)alkylthio, phenyl, hydroxy-(1-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl or (l-4C)alkylthio-(l-4C)alkyl; and R 5 , Ar 1 , A 1 , X 1 , Ar 2 , R 1 , R 2 and R 3 have any of the meanings defined hereinbefore or in this section defining particular compounds; (b) R 5 is hydrogen, (l-4C)alkyl, (3-4C)alkenyl, (3-4C)alkynyl, (2-5C)alkanoyl, halogeno-(2-4C)alkyl, hydroxy-(2-4C)alkyl, (l-4C)alkoxy-(2-4C)alkyl, cyano-(1-4C)alkyl, carboxy-(l-4C)alkyl, (l-4C)alkoxycarbonyl-(l-4C)alkyl, phenyl-(1-4C)alkyl or (2-5C)alkanoyl-(l-4C)alkyl; and R 4 , Ar 1 , A 1 , X 1 , Ar 2 , R 1 , R 2 and R 3 have any of the meanings defined hereinbefore or in this section defining particular compounds; (c) R is heteroaryl-(1-4C)alkyl (especially imidazolyl- or thiazolyl-(l-4C)alkyl) and wherein each heteroaryl group may optionally bear one or two substituents selected from halogeno, (1-4C)alkyl and (l-4C)alkoxycarbonyl; and R 4 , Ar 1 , A 1 , X 1 , Ar 2 , R 1 , 2 3 R and R have any of the meanings defined hereinbefore or in this section defining particular compounds; 5 (d) R is heteroaryl-(1-4C)alkyl (especially pyridyl-(l-4C)alkyl); and R 4 , Ar 1 , A 1 , X 1 , Ar 2 , R 1 , R 2 and R 3 have any of the meanings defined hereinbefore or in this section defining particular compounds; (e) Ar is phenylene which may optionally bear one or two substituents selected from halogeno, (1-4C)alkyl and (l-4C)alkoxy; and / ι 1 1 . R , R , A , X , Ar , R , R and R have any of the meanings defined hereinbefore or in this section defining particular compounds; (f) Ar is 1,3- or 1,4-phenylene which may optionally bear a substituent selected from halogeno, hydroxy, (l-4C)alkyl, (l-4C)alkoxy and phenyl-(l-4C)alkoxy; and R 4 , R 5 , A 1 , X 1 , Ar 2 , R 1 , R 2 and R 3 have any of the meanings defined hereinbefore or in this section defining particular compounds; (g) Ar is 2,5-pyridinediyl, 2,5-pyrazinediyl or / c ι ι 0 1 0 O 3,6-pyridazinediyl; and R , R , A , X , Ar , R , R and R have any of the meanings defined hereinbefore or in this section defining particular compounds; (h) Ar 1 is phenylene and R4 is an ethylene group linked to Ar1 at the position ortho to the -N=C(R )- group; and R , A , X , Ar , R , 2 3 R and R have any of the meanings defined hereinbefore or in this section defining particular compounds; 1 4 1 (i) Ar is 1,4-phenylene and R is linked to Ar ortho to the 4 -N=C(R )- group and defines an ethylene or vinylene group, or a group of the formula -(CH„) -X 3 - 2'n wherein n is 2 and X 3 is oxy; and R5, A1, X1, Ar2, R1, R2 and R3 have any of the meanings defined hereinbefore or in this section defining particular compounds; (j) A 1 is a direct link to X 1 ; and R 4 , R 5 , Ar 1 , X 1 , Ar 2 , R 1 , R 2 3 and R have any of the meanings defined hereinbefore or in this section defining particular compounds; (k) A 1 is (l-4C)alkylene and X 1 is oxy; and R 4 , R 5 , Ar 1 , Ar 2 , 1 2 3 R , R and R have any of the meanings defined hereinbefore or in this section defining particular compounds; (1) A is a direct link to X and X is thio; and R , R , Ar , 2 1 2 3 Ar , R , R and R have any of the meanings defined hereinbefore or in this section defining particular compounds; 2 (m) Ar is phenylene which may optionally bear one or two substituents selected from halogeno, trifluoromethyl, amino, 2 (1-4C)alkyl and (l-4C)alkoxy, or Ar is pyridinediyl or thiophenediyl; Λ c 1 1 1 1 9 . and R , R , Ar , A , X , R , R and R have any of the meanings defined hereinbefore or in this section defining particular compounds; 2 (n) Ar is 1,3-phenylene which may optionally bear one or two c 1 1 1 1 0 halogeno substituents; and R , R , Ar , A , X , R , R and R have any of the meanings defined hereinbefore or in this section defining particular compounds; 2 (o) Ar is pyrimidinediyl which may optionally bear one amino 0 / -s 1 substituent or Ar is thiophenediyl or thiazolediyl; and R , R , Ar , 1 1 1 2 3 A , X , R , R and R have any of the meanings defined hereinbefore or in this section defining particular compounds; (p) R is hydrogen; and R , R , Ar , A , X , Ar , R and R have any of the meanings defined hereinbefore or in this section defining particular compounds; or 2 3 2 2 3 (q) R and R together form a group of the formula -A -X -A - 2 3 which together with the carbon atom to which A and A are attached define a ring having 5 or 6 ring atoms, wherein each of A 2 and A3 is 2 independently (l-3C)alkylene and X is oxy, and which ring may optionally bear one or two (1-4C)alkyl substituents; and R , R , Ar , 1 1 2 1 A , X Ar and R have any of the meanings defined hereinbefore or in this section defining particular compounds. A further preferred compound of the invention comprises an oxime derivative of the formula I 4 wherein R is hydrogen, cyano, trifluoromethyl, dimethylamino, methyl, ethyl, propyl, isopropyl, acetyl, methoxycarbonyl, ethoxycarbonyl, methylthio, phenyl, hydroxymethyl, methoxymethyl or methylthiomethyl; R is hydrogen, methyl, ethyl, propyl, isopropyl, allyl, prop-2-ynyl, acetyl, propionyl, butyryl, pivaloyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, cyanomethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyl, acetonyl or 2-, 3- or 4-pyridylmethyl; Ar is 1,4-phenylene which may optionally bear one substituent selected from fluoro, chloro, hydroxy, methyl, methoxy and benzyloxy, or Ar is 2,5-pyridinediyl, or Ar is 1,4-phenylene and R is linked to Ar ortho to the -N=C(R )- group and defines an ethylene or vinylene group, or a group of the formula -CH 2 CH 2 0- A is a direct link to X and X is thio or sulphonyl, or A is methylene and X is oxy; 2 Ar is 1,3-phenylene which may optionally bear one or two fluoro 2 substituents or Ar is 3,5-pyridinediyl, 2-amino-4,6-pyrimidinediyl, 2,4- or 2,5-thiophenediyl or 2,4- or 2,5-thiazolediyl; R is hydrogen; and R 2 and R3 together form a group of the formula -A2-X2-A3- which 2 3 together with the carbon atom to which A and A are attached define a 2 3 ring having 5 or 6 ring atoms, wherein A is methylene or ethylene, A 2 is ethylene and X is oxy, and which ring may optionally bear one or two substituents selected from methyl and ethyl; or a pharmaceutically-acceptable salt thereof. A further preferred compound of the invention comprises an oxime derivative of the formula I 4 wherein R is hydrogen, cyano, trifluoromethyl, dimethylamino, methyl, ethyl, propyl, isopropyl, acetyl, methoxycarbonyl, ethoxycarbonyl, methylthio or phenyl; R is hydrogen, methyl, ethyl, propyl, isopropyl, allyl, prop-2-ynyl, acetyl, propionyl, butyryl, pivaloyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, cyanomethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl or 2-, 3- or 4-pyridylmethyl; Ar is 1,4-phenylene which may optionally bear one substituent selected from fluoro, chloro, hydroxy, methyl, methoxy and benzyloxy; 1 4 1 4 or Ar is 1,4-phenylene and R is linked to Ar ortho to the -N=C(R )- group and defines an ethylene or vinylene group, or a group of the formula -CH 2 CH 2 0-; A is a direct link to X and X is thio or sulphonyl, or A is methylene and X is oxy; 2 Ar is 1,3-phenylene which may optionally bear one or two fluoro 2 substituents, or Ar is 3,5-pyridinediyl, 2-amino-4,6-pyrimidinediyl, 2,4- or 2,5-thiophenediyl or 2,4- or 2,5-thiazolediyl; R is hydrogen; 2 3 2 2 3 and R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 ring having 5 or 6 ring atoms, wherein A is methylene or ethylene, A 2 is ethylene and X is oxy, and which ring may optionally bear one or two substituents selected from methyl and ethyl; or a pharmaceutically-acceptable salt thereof. A further preferred compound of the invention comprises an oxime derivative of the formula I 4 wherein R is methyl, ethyl, isopropyl, hydroxymethyl or methoxymethyl; R is hydrogen, methyl, allyl, prop-2-ynyl, acetyl, pivaloyl, 2-hydroxyethyl, cyanomethyl, acetonyl, 3-pyridylmethyl or 4-pyridylmethyl; Ar is 1,4-phenylene or 2,5-pyridinediyl (with the X group in the 2-position); A is a direct link to X and X is thio or sulphonyl; 2 Ar is 1,3-phenylene, 5-fluoro-l,3-phenylene, 2,4-thiophenediyl (with the X group in the 2-position), 2,4-thiazolediyl (with the X group in the 2-position) or 2,5-thiazolediyl (with the X group in the 2-position) ; R is hydrogen; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 ring having 5 or 6 ring atoms, wherein A is methylene or ethylene, A 2 is ethylene and X is oxy, and which ring may optionally bear a methyl 2 substituent alpha to X ; or a pharmaceutically-acceptable salt thereof. A further preferred compound of the invention comprises an oxime derivative of the formula I wherein R is hydrogen, methyl, acetyl, pivaloyl, cyanomethyl, 3-pyridylmethyl or 4-pyridylmethyl; )- group and defines an ethylene group, or a group of the formula -CH 2 CH 2 0-; A is a direct link to X and X is thio, or A is methylene and X is oxy; 2 Ar is 1 , 3-phenylene , 5-fluoro-l , 3-phenylene , 2-amino-4,6-pyrimidinediyl, 2,4-thiophenediyl (with the X group in the 2-position) or 2,5-thiazolediyl (with the X group in the 2-position) ; R is hydrogen; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 ring having 5 or 6 atoms, wherein A is methylene or ethylene, A is 2 ethylene and X is oxy, and which ring may optionally bear a methyl 2 substituent alpha to X ; or a pharmaceutically-acceptable salt thereof. A further preferred compound of the invention comprises an oxime derivative of the formula I 4 wherein R is methyl; R is hydrogen, methyl, prop-2-ynyl, acetyl, pivaloyl or cyanomethyl; Ar is 1,4-phenylene; A is a direct link to X and X is thio or sulphonyl; 2 Ar is 1,3-phenylene, 5-fluoro-l,3-phenylene, 2,5-difluoro-l,3-phenylene or 2,4-thiophenediyl (with the X group in the 2-position); R is hydrogen; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 2 ring having 6 ring atoms, wherein each of A and A is ethylene and X is oxy, and which ring may optionally bear a methyl substituent alpha to X 2 ; or a pharmaceutically-acceptable salt thereof. A specific especially preferred compound of the invention is, for example, the following oxime derivative of the formula I:- (E)-4'-{5-fluoro-3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4- yl]phenylthio}acetophenone oxime; or a pharmaceutically-acceptable salt thereof. A further specific especially preferred compound of the invention is, for example, the following oxime derivative of the formula I:- ( , E) -4 / - {5-fluoro-3- [ (2S , 4R) -4-hydroxy-2-methyltetrahydropyran-4-yl] - phenylsulphonylj acetophenone oxime , ( E_) -4 ' - {5-f luoro-3- [ ( 2S , 4R) -4-hydroxy-2-methyltetrahydropyran-4-yl] - phenylsulphonyl} acetophenone oxime O-cyanomethyl ether, ( E) -4 ' - {3- [ (2S , 4R) -4-hydroxy-2-methyltetrahydropyran-4-yl] phenylthio} - acetophenone oxime 0-methyl ether, (E)-4'-{3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]phenyl- sulphonyl}acetophenone oxime O-cyanomethyl ether, (E)-4'-{3-[(2S, R)-4-hydroxy-2-methyltetrahydropyran-4-yl]phenyl- sulphonyl}acetophenone oxime 0-methyl ether, (E)-4'-{4-[ (2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]thien-2- ylthio}acetophenone oxime, (E)-4'-{4-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]thien-2- ylthio}acetophenone oxime O-cyanomethyl ether, (E)-4'-{4-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]thien-2- ylsulphonyl}acetophenone oxime O-cyanomethyl ether or (E)-4'-{4-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]thien-2- ylsulphonyl}acetophenone oxime; or a pharmaceutically-acceptable salt thereof. A compound of the invention comprising an oxime derivative of the formula I, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of structurally-related compounds. Such procedures are provided as a further feature of the invention and are illustrated by the following 4 5 representative examples in which, unless otherwise stated, R , R , 1 1 1 2 1 2 3 Ar , A , X , Ar , R , R and R have any of the meanings defined hereinbefore, provided that when there is an amino, imino, alkylamino, i / c 1 0 0 carboxy or hydroxy group in R , R , R , Ar , Ar , R or R then any such group may optionally be protected by a conventional protecting group which may be removed when so desired by conventional means, (a) The reaction, conveniently in the presence of a suitable base, of a compound of the formula II OR 1 0=C(R ) -Ar 1 -A 1 -X 1 -Ar 2 -C-R 2 II R 3 with a hydroxylamine of the formula R 0-NH„. A suitable base for the reaction is, for example, an alkali or alkaline earth metal carbonate, (l-4C)alkoxide, (l-4C)alkanoate, hydroxide or hydride, for example sodium carbonate, potassium carbonate, barium carbonate, sodium ethoxide, potassium butoxide, sodium acetate, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride. Alternatively a suitable base for the reaction is, for example, an organic amine base such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene. The reaction is conveniently performed in a suitable inert solvent or diluent, for example, one or more of water, a (l-4C)alcohol such as methanol, ethanol and propanol, pyridine, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxan or a dipolar aprotic solvent such as N,N-dimethylformamide and dimethylsulphoxide. The reaction is conveniently performed at a temperature in the range, for example, 10 to 150°C, conveniently at or near 70°C. The starting materials of the formula II may be obtained by standard procedures of organic chemistry which are within the ordinary skill of an organic chemist. The disclosures of European Patent Applications Nos. 0375404, 0385662, 0409413 and 0420511 are particularly relevant to the preparation of suitable starting materials. (b) For the production of those compounds of the formula I 5 wherein R is (1-4C)alkyl or substituted-alkyl, the alkylation, conveniently in the presence of a suitable base as defined hereinbefore, of an oxime of the formula III OR 1 H0-N=C(R 4 ) -Ar 1 -A 1 -X 1 -Ar 2 -C-R 2 III R 3 with an alkylating agent of the formula R -Z, wherein Z is a displaceable group. A suitable displaceable group Z is, for example, a halogeno or sulphonyloxy group, for example a chloro, bromo, iodo, methanesulphonyloxy or toluene-4-sulphonyloxy group. The reaction is conveniently performed in a suitable inert solvent or diluent, for example N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetone, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxan or methylene chloride, anτJ at a temperature in the range, for example, -10 to 150°C, conveniently at or near ambient temperature. The starting materials of the formula III may be obtained by the process of paragraph (a) hereinbefore utilising a hydroxylamine of the formula R 0-NH- wherein R is hydrogen. The preparation of such starting materials is described within the accompanying non-limiting Examples. (c) For the production of those compounds of the formula I wherein R is (2-5C)alkanoyl, carbamoyl, N-(l-4C)alkylcarbamoyl or N,N-di-(l~4C)alkylcarbamoyl, the acylation, conveniently in the presence of a suitable base as defined hereinbefore, of an oxime of the formula III OR 1 I H0-N=C(R 4 )-Ar 1 -A 1 -X 1 -Ar 2 -C-R 2 III R3 with an acylating agent of the formula R -Z, wherein Z is a displaceable group as defined hereinbefore. The reaction is conveniently performed in a suitable inert solvent or diluent as defined in paragraph (b) hereinbefore, and at a temperature in the range, for example, -10 to 150°C, conveniently at or near ambient temperature. (d) For the production of those compounds of the formula I 4 wherein R is cyano or (2-5C)alkanoyl, the reaction, conveniently in the presence of a suitable base as defined hereinbefore, of a compound of the formula IV OR 1 I R 4 -CH 2 -Ar 1 -A 1 -X 1 -Ar 2 -C-R 2 IV I R 3 with an alkylnitrite. A suitable alkylnitrite is, for example, isopentylnitrite. The reaction is conveniently performed in a suitable inert solvent or diluent as defined in paragraph (b) hereinbefore, and at a temperature in the range, for example, 10 to 100°C, conveniently at or near 50°C. The starting materials of the formula IV may be obtained by standard procedures of organic chemistry. (e) For the production of those compounds of the formula I 4 wherein R is amino, (1-4C)alkylamino, di-(l-4C)alkylamino or (l-4C)alkylthio, the alkylation of ammonia, a (l-4C)alkylamine, a di-(l-4C)alkylamine or a (l-4C)alkanethiol with an alkylating agent of the formula V OR 1 I R 5 0-N=C(Z)-Ar 1 -A 1 -X 1 -Ar 2 -C-R 2 V I R 3 wherein Z is a displaceable group as defined hereinbefore. The reaction is conveniently performed in a suitable inert solvent or diluent as defined in paragraph (b) hereinbefore, and at a temperature in the range, for example, 10 to 100°C, conveniently at or near ambient temperature. The starting material of the formula V may be obtained by standard procedures of organic chemistry, (f) The coupling of a compound of the formula VI R 5 0-N=C(R )-Ar 1 -A 1 -X 1 -Z VI wherein Z is a displaceable group as defined hereinbefore, or alternatively, when X is a thio group, Z may be a group of the formula R 5 0-N=C(R 4 )-Ar 1 -A 1 -X 1 - with an organometallic reagent of the formula VII OR M-Ar -C-R VII R 3 wherein M is an alkali metal or alkaline earth metal such as lithium or calcium or M represents the magnesium halide portion of a conventional Grignard reagent. The coupling reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, -80 to +50°C, conveniently in the range -80°C to ambient temperature. The preparation of the starting materials of the formulae VI and VII may be obtained by standard procedures of organic chemistry. (g) For the production of those compounds of the formula I 1 2 3 wherein X is a sulphinyl or sulphonyl group, or wherein R and R 2 2 3 2 together form a group of the formula -A -X -A - and X is a sulphinyl or sulphonyl group, the oxidation of a compound of the formula I 1 2 3 wherein X is a thio group, or wherein R and R together form a group 2 2 3 2 of the formula -A -X -A - and X is a thio group. A suitable oxidising agent is, for example, any agent known in the art for the oxidation of thio to sulphinyl and/or sulphonyl, for example, hydrogen peroxide, a peracid (such as 3-chloroperoxybenzoic or peroxyacetic acid) , an alkali metal peroxysulphate (such as potassium peroxymonosulphate) , chromium trioxide or gaseous oxygen in the presence of platinum. The oxidation is generally carried out under as mild conditions as possible and with the required stoichiometric amount of oxidising agent in order to reduce the risk of over oxidation and damage to other functional groups. In -general the reaction is carried out in a suitable solvent or diluent such as methylene chloride, chloroform, acetone, tetrahydrofuran or tert-butyl methyl ether and at a temperature, for example, at or near ambient temperature, that is in the range 15 to 35°C. When a compound carrying a sulphinyl group is required a milder oxidising agent may also be used, for example sodium or potassium metaperiodate, conveniently in a polar solvent such as acetic acid or ethanol. It will be appreciated that when a compound of the formula I containing a sulphonyl group is required, it may be obtained by oxidation of the corresponding sulphinyl compound as well as of the corresponding thio compound. (h) For the production of those compounds of the formula I wherein R is a carboxy-(l-4C)alkyl group, the hydrolysis of a compound of the formula I wherein R is a (l-4C)alkoxycarbonyl-(l-4C)alkyl group. The hydrolysis is conveniently performed in the presence of a suitable base as defined hereinbefore. Alternatively when the (l-4C)alkoxycarbonyl group is, for example, a tert-butoxycarbonyl group, the hydrolysis may be performed in the presence of a suitable acid as defined hereinbefore. The reaction is conveniently performed in a suitable solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 150°C, conveniently at or near 50°C. Conventional protecting groups for an amino, imino, alkylamino, carboxy or hydroxy group which may be present in R , R , 5 1 2 2 3 R , Ar , Ar or the ring defined by R and R are set out hereinafter. A suitable protecting group for an amino, imino or alkylamino group is, for example, an acyl group for example a (2-4C)alkanoyl group (especially acetyl), a (l-4C)alkoxycarbonyl group (especially methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl) , an arylmethoxycarbonyl group (especially benzyloxycarbonyl) or an aroyl group (especially benzoyl). The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-charcoal. A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a (l-4C)alkyl group (especially methyl or ethyl) which may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide; or, for example, a tert-butyl group which may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid. A suitable protecting group for a hydroxy group is, for example, an acyl group, for example a (2-4C)alkanoyl group (especially acetyl), an aroyl group (especially benzoyl) or an arylmethyl group (especially benzyl). The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-charcoal. When a pharmaceutically-acceptable salt of a compound of the formula I is required, it may be obtained, for example, by reaction of said compound with a suitable acid or base using a conventional procedure. When an optically active form of a compound of the formula I is required, it may be obtained by carrying out one of the aforesaid procedures using an optically active starting material, or by resolution of a racemic form of said compound using a conventional procedure. Many of the intermediates defined herein are novel, for example, those of the formula II and these are provided as a further feature of the invention. Moreover we have discovered that compounds of the formula II as defined hereinbefore are not only novel chemical intermediates but are also effective inhibitors of the enzyme 5-LO and thus of leukotriene biosynthesis. Accordingly these novel compounds, or pharmaceutically-acceptable salts thereof, are provided as a further feature of the invention. As stated previously, the compounds of the formula I are inhibitors of the enzyme 5-L0. The effects of this inhibition may be demonstrated using one or more of the standard procedures set out below:- a) An in vitro assay system involving incubating a test compound with heparinised human blood, prior to challenge with the calcium ionophore A23187 and then indirectly measuring the inhibitory effects on 5-L0 by assaying the amount of LTB, using specific radioimmunoassays described by Carey and Forder (Prostaglandins, Leukotrienes Med. , 1986, 22 ^ , 57; Prostaglandins, 1984, 28, 666; Brit. J. Pharmacol., 1985, 84, 34P) which involves the use of a protein-LTB, conjugate produced using the procedure of Young et alia (Prostaglandins, 1983, 26(4), 605-613). The effects of a test compound on the enzyme cyclooxygenase (which is involved in the alternative metabolic pathway for arachidonic acid and gives rise to prostaglandins, thromboxanes and related metabolites) may be measured at the same time using the specific radioimmunoassay for thromboxane B 2 (TxB 2 ) described by Carey and Forder (see above). This test provides an indication of the effects of a test compound against 5-LO and also cyclooxygenase in the presence of blood cells and proteins. It permits the selectivity of the inhibitory effect on 5-LO or cyclooxygenase to be assessed. b) An ex vivo assay system, which is a variation of test a) above, involving administration to a group of rats of a test compound (usually orally as the suspension produced when a solution of the test compound in dimethylsulphoxide is added to carboxymethylcellulose) , blood collection, heparinisation, challenge with A23187 and radioimmunoassay of LTB, and TxB_. This test provides an indication of the bioavailability of a test compound as an inhibitor of 5-LO or cyclooxygenase. c) An in vivo system involving measuring the effects of a test compound administered orally against the liberation of LTB, induced by zymosan within an air pouch generated within the subcutaneous tissue of the back of male rats. The rats are anaesthetised and air pouches are formed by the injection of sterile air (20ml). A further injection of air (10ml) is similarly given after 3 days. At 6 days after the initial air injection the test compound is administered (usually orally as the suspension produced when a solution of the test compound in dimethylsulphoxide is added to hydroxypropylmethylcellulose), followed by the intrapouch injection of zymosan (1ml of a 1% suspension in physiological saline). After 3 hours the rats are killed, the air pouches are lavaged with physiological saline, and the specific radioimmunoassay described above is used to assay LTB, in the washings. This test provides an indication of inhibitory effects against 5-L0 in an inflammatory milieu. Although the pharmacological properties of the compounds of the formula I vary with structural changes as expected, in general compounds of the formula I possess 5-L0 inhibitory effects at the following concentrations or doses in one or more of the above tests a)-c):- Test a): IC 5Q (LTB.) in the range, for example, 0.01-40μM IC 5Q (TxB 2 ) in the range, for example, 40-200μM; Test b): oral ED 5Q (LTB.) in the range, for example, 0.1-lOOmg/kg; Test c): oral EDc 0 (LTB.) in the range, for example, 0.1-50mg/kg. No overt toxicity or other untoward effects are present in tests b) and/or c) when compounds of the formula I are administered at several multiples of their minimum inhibitory dose or concentration. Thus, by way of example, the compound (E)-4'-{5-fluoro-3- [(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]phenylthioJacetophenone oxime has an IC,- 0 of 0.07μM against LTB, in test a) and an oral ED of approximately 0.05 mg/kg versus LTB, in test c). In general those compounds of the formula I which are particularly preferred have an IC 50 of <lμtf against LTB, in test a) and an oral ED of <10 mg/kg against LTB, in tests b) and/or c). These compounds are examples of compounds of the invention which show selective inhibitory properties for 5-LO as opposed to cyclooxygenase, which selective properties are expected to impart improved therapeutic properties, for example, a reduction in or freedom from the gastrointestinal side-effects frequently associated with cyclooxygenase inhibitors such as indomethacin. According to a further feature of the invention there is provided a pharmaceutical composition which comprises an oxime derivative of the formula I, or a pharmaceutically- acceptable salt thereof, in association with a pharmaceutically- acceptable diluent or carrier. According to a further feature of the invention there is provided a pharmaceutical composition which comprises a compound of the formula II, or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier. The composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use, for example a cream, ointment, gel or aqueous or oily solution or suspension; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example as a finely divided powder such as a dry powder, a microcrystalline form or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension. In general the above compositions may be prepared in a conventional manner using conventional excipients. The amount of active ingredient (that is an oxime derivative of the formula I, or a pharmaceutically-acceptable salt thereof, or a compound of the formula II, or a pharmaceutically-acceptable salt thereof) that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation -intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. According to a further feature of the invention there is provided an oxime derivative of the formula I, or a pharmaceutically-acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy. The invention also includes a method of treating a disease or medical condition mediated alone or in part by one or more leukotrienes which comprises administering to a warm-blooded animal requiring such treatment an effective amount of an active ingredient as defined above. The invention also provides the use of such an active ingredient in the production of a new medicament for use in a leukotriene mediated disease or medical condition. The size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. As mentioned above, compounds of the formula I are useful in treating those allergic and inflammatory conditions which are due alone or in part to the effects of the metabolites of arachidonic acid arising by the linear (5-L0 catalysed) pathway and in particular the leukotrienes, the production of which is mediated by 5-L0. As previously mentioned, such conditions include, for example, asthmatic conditions, allergic reactions, allergic rhinitis, allergic shock, psoriasis, atopic dermatitis, cardiovascular and cerebrovascular disorders of an inflammatory nature, arthritic and inflammatory joint disease, and inflammatory bowel diseases. In using a compound of the formula I for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.5 mg to 75 mg per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.5 mg to 30 mg per kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.5 mg to 25 mg per kg body weight will be used. Although the compounds of the formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man) , they are also useful whenever it is required to inhibit the enzyme 5-LO. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. By virtue of their effects on leukotriene production, the compounds of the formula I have certain cytoprotective effects, for example they are useful in reducing or suppressing certain of the adverse gastrointestinal effects of the cyclooxygenase inhibitory non- steroidal anti-inflammatory agents (NSAIA) , such as indomethacin, acetylsalicylic acid, ibuprofen, sulindac, tolmetin and piroxicam. Furthermore, co-administration of a 5-L0 inhibitor of the formula I with a NSAIA can result in a reduction in the quantity of the latter agent needed to produce a therapeutic effect, thereby reducing the likelihood of adverse side-effects. According to a further feature of the invention there is provided a pharmaceutical composition which comprises an oxime derivative of the formula I, or a pharmaceutically- acceptable salt thereof as defined hereinbefore, in conjunction or admixture with a cyclooxygenase inhibitory non-steroidal anti- inflammatory agent (such as those mentioned above), and a pharmaceutically-acceptable diluent or carrier. The cytoprotective effects of the compounds of the formula I may be demonstrated, for example in a standard laboratory model which assesses protection against indomethacin-induced or ethanol-induced ulceration in the gastrointestinal tract of rats. The compositions of the invention may in addition contain one or more therapeutic or prophylactic agents known to be of value for the disease under treatment. Thus, for example a known platelet aggregation inhibitor, hypolipidemic agent, anti-hypertensive agent, beta-adrenergic blocker or a vasodilator may usefully also be present in a pharmaceutical composition of the invention for use in treating a heart or vascular disease or condition. Similarly, by way of example, an anti-histamine, steroid (such as beclomethasone dipropionate) , sodium cromoglycate, phosphodiesterase inhibitor or a beta-adrenergic stimulant may usefully also be present in a pharmaceutical composition of the invention for use in treating a pulmonary disease or condition. The invention will now be illustrated in the following non-limiting Examples in which, unless otherwise stated:- (i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids by filtration; (ii) operations were carried out at ambient temperature, that is in the range 18-25°C and under an atmosphere of an inert gas such as argon; (iii) column chromatography (by the flash procedure) and medium pressure liquid chromatography (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck, Darmstadt, Germany; (iv) yields are given for illustration only and are not necessarily the maximum attainable; (v) the structures of the end-products of the formula I were confirmed by NMR and mass spectral techniques; unless otherwise stated, CDC1, solutions of the end-products of the formula I were used for the determination of the NMR spectral data, chemical shift values were measured on the delta scale and the following abbreviations are used: s, singlet; d, doublet; t, triplet; m, multiplet; (vi) intermediates were not generally fully characterised and purity was assessed by thin layer chromatographic, infra-red (IR) or NMR analysis; (vii) melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the formula I were determined after recrystallisation from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in admixture; (viii) the oxime derivatives disclosed in the accompanying Examples have not been positively identified as the (E)-geometric isomer, although it is believed, based on conventional precedent that the major product in each case, as obtained substantially free from the other isomer by chromatographic purification, will have the (E)-configuration; (ix) the following abbreviations have been used:- THF tetrahydrofuran; DMSO dimethylsulphoxide; NMP N-methylpyrrolidin-2-one; DMF N,N-dimethylformamide. Example 1 A mixture of 4'-{5-fluoro-3-[ (2S,4R)-4-hydroxy-2- methyltetrahydropyran-4-yl]phenylthioJacetophenone (0.08 g) , hydroxylamine hydrochloride (0.05 g), sodium acetate (0.08 g) and ethanol (2 ml) was stirred and heated to reflux for 2 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO,) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained (E)-4'-{5-fluoro-3- [(2S, R)-4-hydroxy-2-methyltetrahydropyran-4-yl]-phenylthio}- acetophenone oxime (0.066 g, 79%) as a gum; NMR Spectrum: 1.22 (d, 3H), 1.6-1.75 (m, 3H) , 2.05 (m, 1H) , 2.3 (m, 3H), 3.85-4.05 (m, 3H) , 6.85 (m, 1H) , 7.05 (m, 1H), 7.28 (m, 1H) , 7.38 (m, 2H), 7.62 (m, 2H), 7.8 (broad s, 1H). The 4'-{5-fluoro-3-[(2S,4R)-4-hydroxy-2-methyltetrahydro- pyran-4-yl]phenylthio}acetophenone used as a starting material was obtained as follows:- A mixture of sodium hydrosulphide hydrate (NaSH, 33.6 g) and N-methylmorpholine (220 ml) was stirred and heated to 160°C. The mixture was partially evaporated under vacuum to remove the water. A solution of 4'-bromoacetophenone (40 g) in N-methylpyrrolidin-2-one (30 ml) was added dropwise to the residue and the mixture was stirred and heated to 160°C for 90 minutes. The mixture was evaporated and the residue was poured into a mixture of ethyl acetate, water and ice. The aqueous phase was acidified to pH2 by the addition of dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine, dried (MgSO,) and evaporated. There was thus obtained 4'-mercaptoacetophenone as an oil (25 g) which was used without further purification. A solution of the oil so obtained in DMSO (100 ml) was stirred at ambient temperature for 16 hours. The mixture was poured onto a mixture of ice and water and extracted with ethyl acetate. The organic extract was washed with brine, dried (MgSO^) and evaporated. The residue was purified by column chromatography using a 7:3 mixture of petroleum ether (b.p. 40-60°C) and ethyl acetate as eluent. There was thus obtained di-(4-acetylphenyl) disulphide (16.3 g, 65%), m.p. 94-95°C. A mixture of di-(4-acetylphenyl) disulphide (1.9 g), ethylene glycol (2.45 ml), triethyl orthoformate (5 ml), 4-toluenesulphonic acid (0.041 g) and toluene (22 ml) was stirred and heated to 45°C for 2 hours. The mixture was cooled to ambient temperature, washed with a saturated aqueous sodium bicarbonate solution, dried (MgSO.) and evaporated. The residue was purified by column chromatography using a 3:7 mixture of petroleum ether (b.p. 40-60°C) and ethyl acetate as eluent. There was thus obtained di-[4-(2-methyl-l,3-dioxolan-2-yl)- phenyl] disulphide (2.12 g, 99%), m.p. 135-137°C. A mixture of di-[4-(2-methyl-l,3-dioxolan-2-yl)phenyl] disulphide (2 g), triphenylphosphine (1.41 g), water (3 ml) and 1,4-dioxan (20 ml) was stirred and heated to 70°C for 7 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and IN aqueous sodium hydroxide solution. The aqueous phase was acidified to pH6 by the addition of 6N aqueous hydrochloric acid and extracted with diethyl ether. The organic phase was washed with brine, dried (MgSO,) and evaporated. There was thus obtained 4-(2-methyl-l,3-dioxolan-2-yl)benzenethiol (1.4 g, 70%) as an oil. After appropriate repetition of the above-mentioned steps a mixture of the thiol so obtained (9.8 g) , l-bromo-3,5-difluorobenzene (11.6 g), lithium hydroxide hydrate (2.52 g) and NMP (30 ml) was stirred and heated to 75 C for 18 hours. The mixture was cooled to ambient temperature and partitioned between diethyl ether and water. The organic phase was washed with brine, dried (MgSO,) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained 5-fluoro-3-[4-(2-methyl-l,3-dioxolan-2-yl)phenylthio]- bromobenzene (13.36 g, 72%), m.p. 62-64 C. n-Butyl-lithium (1.5M in hexane, 1.8 ml) was added dropwise to a stirred solution of a portion (1 g) of the bromobenzene so obtained in THF (20 ml) which had been cooled to -70 C. The mixture was stirred at -70°C for 30 minutes. A solution of (2S)-2-methyl- tetrahydropyran-4-one [European Patent Application No. 0385662 (Example 20 thereof), 0.228 g] in THF (1 ml) was added. The mixture was stirred, allowed to warm to ambient temperature and stirred at that temperature for 2 hours. Glacial acetic acid (2 ml) was added and the mixture was partitioned between diethyl ether and water. The organic phase was washed with brine, dried (MgSO.) and evaporated. A solution of the residue in diethyl ether (5 ml) was added to a mixture of water (13 ml) and concentrated sulphuric acid (7 ml) which had been cooled in an ice bath. The mixture was stirred at ambient temperature for 18 hours. The mixture was recooled in an ice bath and concentrated sulphuric acid (2 ml) was added dropwise. The mixture was stirred at ambient temperature for a further 6 hours. The mixture was poured onto ice and extracted with diethyl ether. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and with brine, dried (MgSO,) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained 4'-{5-fluoro-3- [(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]phenylthio}- acetophenone (0.21 g, 31%) as an oil; NMR Spectrum: 1.21 (d, 3H), 1.6-1.75 (m, 3H) , 2.0-2.2 (m, 1H) , 2.57 (m, 3H), 3.85-4.05 (m, 3H) , 7.0 (m, 1H), 7.19 (m, 1H) , 7.3 (m, 2H), 7.36 (m, 1H), 7.87 (m, 2H). Example 2 Using an analogous procedure to that described in Example 1, 4'-{5-fluoro-3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]phenyl- sulphonyl}acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-{5-fluoro-3-[ (2S,4R)-4-hydroxy-2-methyltetrahydropyran-4- yljphenylsulphonyl}acetophenone oxime in 84% yield, m.p. 176-177°C (recrystallised from a mixture of hexane and ethyl acetate); NMR Spectrum: 1.22 (d, 3H), 1.55-1.75 (m, 3H), 1.82 (s, 1H), 2.0 (m, 1H), 2.3 (s, 3H), 3.85-4.05 (m, 3H) , 7.4 (m, 1H), 7.52 (m, 1H), 7.7-7.85 (m, 3H) , 7.88-8.0 (m, 3H). The 4'-{5-fluoro-3-[(2S,4R)-4-hydroxy-2-methyltetrahydro- pyran-4-yl]phenylsulphonyl}acetophenone used as a starting material was obtained as follows:- A mixture of 4'-{5-fluoro-3-[(2S,4R)-4-hydroxy-2-methyltetra- hydropyran-4-yl]phenylthio}acetophenone (1.8 g) , potassium peroxymonosulphate (4 g), water (20 ml) and ethanol (50 ml) was stirred at ambient temperature for 3 hours. Water (100 ml) was added and the mixture was extracted with ethyl acetate. The organic phase was dried (MgSO,) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained the required starting material (1.57 g, 80%), m.p. 110-111°C (recrystallised from hexane and ethyl acetate). Example 3 Sodium hydride (50% dispersion in mineral oil, 0.02 g) was added portionwise to a stirred mixture of (E)-4'-{5-fluoro-3-[(2S,4R)- 4-hydroxy-2-methyltetrahydropyran-4-yl]phenylthio}acetophenone oxime (0.13 g), bromoacetonitrile (0.1 g) and DMF (2 ml) which had been cooled in an ice bath. The mixture was allowed to warm to ambient temperature and was stirred for 2 hours. The mixture was partitioned between diethyl ether and water. The organic phase was dried (MgSO,) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained (E)-4'-{5-fluoro-3-[ (2S,4R)-4-hydroxy- 2-methyltetrahydropyran-4-yl]phenylthio}acetophenone oxime O-cyanomethyl ether as a gum (0.135 g, 93%); NMR Spectrum: 1.2 (d, 3H) , 1.6-1.75 (m, 3H), 2.05 (m, 1H) , 2.26 (s, 3H), 3.85-4.05 (m, 3H) , 4.83 (s, 2H), 6.9 (m, 1H) , 7.1 (m, 1H), 7.29 (m, 1H), 7.36 (m, 2H) , 7.64 (m, 2H). Example 4 Using an analogous procedure to that described in Example 3, except that propargyl bromide was used in place of bromoacetonitrile, there was obtained (E)-4'-{5-fluoro-3-[(2S,4R)-4-hydroxy-2-methyltetra- hydropyran-4-yl]phenylthio}acetophenone oxime 0-(2-propynyl) ether in 58% yield; NMR Spectrum: 1.21 (d, 3H), 1.6-1.75 (m, 3H), 2.05 (m, 1H), 2.26 (s, 3H), 2.48 (m, 1H), 3.85-4.05 (m, 3H) , 4.8 (d, 2H), 6.95 (m, 1H), 7.05 (m, 1H), 7.26 (m, 1H) , 7.36 (m, 2H), 7.64 (m, 2H). Example 5 Using an analogous procedure to that described in Example 1, 4'-[2,5-difluoro-3-(4-hydroxytetrahydropyran-4-yl)phenylthio]- acetophenone was reacted with hydroxylamine hydrochloride to give 4'-[2,5-difluoro-3-(4-hydroxytetrahydropyran-4-yl)phenylthio]- acetophenone oxime in 15% yield; NMR Spectrum: 1.7 (d, 2H) , 2.3 (s, 3H), 2.4 (m, 2H), 3.9 (m, 4H) , 6.7 (m, 1H), 7.1 (m, 1H) , 7.4 (d, 2H) , 7.6 (d, 2H) . The 4'-[2,5-difluoro-3-(4-hydroxytetrahydropyran-4-yl)- phenylthio]acetophenone used as a starting material was obtained as follows:- Sodium hydride (60% dispersion in mineral oil, 0.21 g) was added portionwise to a stirred solution of 4-(2-methyl-l,3-dioxolan-2- yl)benzenethiol (1 g) in NMP (5 ml) and the mixture was stirred at ambient temperature for 5 minutes. l-Bromo-2,3,5-trifluorobenzene (1.07 g) was added and the mixture was heated to 90°C for 1 hour. The mixture was tooled to ambient temperature and poured into water (20 ml). The mixture was extracted with diethyl ether. The organic extract was dried (MgSO,) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained 2,5-difluoro-3-[4-(2-methyl-l,3-dioxolan-2-yl)phenylthio]bromobenzene as a gum (1.4 g, 70%) ; NMR Spectrum: (CD 3 S0CD 3 ) 1.55 (s, 3H) , 3.7 (m, 2H) , 4.0 (m, 2H) , 7.0 (m, 1H), 7.5 (m, 4H) , 7.7 (m, 1H) . A solution of the material so obtained in THF (3 ml) was added to a stirred suspension of magnesium (0.036 g) in THF (1 ml) and the formation of a Grignard reagent was initiated by the addition of 1,2-dibromoethane (1 drop). The mixture was stirred and heated to 40°C for 30 minutes. A solution of tetrahydropyran-4-one (0.15 g) in THF (1 ml) was added and the mixture was stirred at 40°C for 20 minutes. The mixture was poured into a saturated aqueous ammonium chloride solution and extracted with diethyl ether. The organic extract was dried (MgSO,) and evaporated. The residue was dissolved in acetone (5 ml) and dilute aqueous hydrochloric acid (1 drop) was added. The mixture was heated to reflux for 2 hours. The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained 4'-[2,5-difluoro-3-(4-hydroxytetrahydropyran-4-yl)phenylthio]- acetophenone (0.16 g, 43%); NMR Spectrum: 1.7 (d, 2H), 2.4 (m, 2H) , 2.6 (s, 3H), 3.9 (m, 4H), 7.0 (m, 1H), 7.25 (m, 1H), 7.35 (d, 2H) , 7.9 (d, 2H) . Example 6 O-Methylhydroxylamine hydrochloride (0.054 g) was added to a stirred mixture of 4'-{3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4- yl]phenylthio}acetophenone (0.2 g) and pyridine (2 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with a 2N aqueous hydrochloric acid solution and with brine, dried (MgSO,) and evaporated. The residue was purified by column chromatography using a 4:1 mixture of petroleum ether (b.p. 40-60°C) and ethyl acetate as eluent. There was thus obtained (E)-4'-{3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]phenylthio}- acetophenone oxime 0-methyl ether as an oil (0.163 g, 75%); NMR Spectrum: 1.21 (d, 3H) , 1.5-1.75 (m, 3H) , 2.08 (m, 1H) , 2.20 (s, 3H), 3.9-4.0 (m, 3H), 3.99 (s, 3H), 7.2-7.4 (m, 5H), 7.5-7.6 (m, 3H) . The 4'-{3-[ (2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]- phenylthio}acetophenone used as a starting material was obtained as follows:- n-Butyl-lithium (1.6M in hexane, 5.3 ml) was added dropwise to a stirred solution of 1,3-dibromobenzene (2 g) in THF (20 ml) which had been cooled to -70°C. The mixture was stirred at -70°C for 30 minutes. A solution of (2S)-2-methyltetrahydropyran-4-one (1.01 g) in THF (5 ml) was added dropwise. The mixture was allowed to warm to ambient temperature and was stirred at that temperature for 3 hours. The mixture was acidified by the addition of glacial acetic acid and was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO,) and evaporated. The residue was purified by column chromatography using a 4:1 mixture of petroleum ether (b.p. 40-60°C) and ethyl acetate as eluent. There were thus obtained:- (2S , 4R) -4-hydroxy-4- (3-bromophenyl) -2-methyltetrahydropyran (0.45 g) and (2S , 4S ) -4-hydroxy-4- ( 3-bromophenyl) -2-methyltetrahydropyran ( 1. 12 g) - The (2S,4S)-isomer was converted into the (2S,4R)-isomer using the following procedure:- A mixture of concentrated sulphuric acid (32.5 ml) and water (17.5 ml) was added to a stirred solution of the (2S,4S)-isomer (1.12 g) in diethyl ether (25 ml) which had been cooled to 0°C. The mixture was stirred at 0°C for 6 hours and at ambient temperature for 1 hour. The mixture was partitioned between diethyl ether and water. The organic phase was washed with brine, dried (MgSO,) and evaporated. The residue was purified by column chromatography using a 4:1 mixture of petroleum ether (b.p. 40-60°C) and ethyl acetate as eluent. There was thus obtained a further portion of (2S,4R)-4-hydroxy-4-(3-bromophenyl)- 2-methyltetrahydropyran (0.75 g). Potassium tert-butoxide (0.316 g) was added portionwise to a stirred solution of 4-(2-methyl-l,3-dioxolan-2-yl)benzenethiol (0.506 g) in DMSO (8 ml) and the mixture was stirred at ambient temperature for 5 minutes. (2S,4R)-4-hydroxy-4-(3-bromophenyl)-2-methyltetrahydro- pyran (0.7 g) and tetrakis(triphenylphosphine)palladium (0.3 g) were added and the mixture was stirred and heated to 115°C for 10 minutes. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO,) and evaporated. The residue was purified by column chromatography using a 5:2 mixture of petroleum ether (b.p. 40-60°C) and ethyl acetate as eluent. There was thus obtained an oil (0.9 g) which was dissolved in acetone (25 ml). A portion (0.6 ml) of 2N aqueous hydrochloric acid was added and the mixture was stirred at ambient temperature for 5 hours. The mixture was neutralised by the addition of 2N aqueous sodium hydroxide solution (0.6 ml). The mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO,) and evaporated. The residue was purified by column chromatography using a 20:9 mixture of petroleum ether (b.p. 40-60°C) and ethyl acetate as eluent. There was thus obtained 4'-{3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]phenyl¬ thio}acetophenone (0.79 g, 99%), m.p. 107-109°C. Example 7 Using an analogous procedure to that described in Example 6, except that hydroxylamine hydrochloride was used in place of O-methylhydroxylamine hydrochloride, there was obtained (E_)-4'-{3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]phenylthio}- acetophenone oxime as an oil in 95% yield; NMR Spectrum: 1.21 (d, 3H) , 1.5-1.75 (m, 3H), 2.1 (m, 1H), 2.26 (s, 3H), 3.9-4.0 (m, 3H) , 7.2-7.4 (m, 5H) , 7.5-7.6 (m, 3H) . Example 8 Sodium hydride (60% dispersion in mineral oil, 0.0134 g) was added to a stirred solution of (E)-4'-{3-[(2S,4R)-4-hydroxy-2-methyl- tetrahydropyran-4-yl]phenylthio}acetophenone oxime (0.1 g) in THF (2 ml). The mixture was stirred at ambient temperature for 10 minutes. Bromoacetonitrile (0.023 ml) was added and the mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO.) and evaporated. The residue was purified by column chromatography using a 5:2 mixture of petroleum ether (b.p. 40-60°C) and ethyl acetate as eluent. There was thus obtained (E)-4'-{3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]- phenylthio}acetophenone oxime O-cyanomethyl ether (0.094 g, 85%); NMR Spectrum: 1.21 (d, 3H) , 1.5-1.75 (m, 3H), 2.1 (m, 1H), 2.24 (s, 3H), 3.9-4.0 (m, 3H), 4.82 (s, 2H) , 7.2-7.4 (m, 5H), 7.5-7.6 (m, 3H) . Example 9 3-Chloroperoxybenzoic acid (60% strength, 0.14 g) was added portionwise to a stirred solution of (E)-4'-{3-[ (2S,4R)-4-hydroxy-2- methyltetrahydropyran-4-yl]phenylthio}acetophenone oxime O-cyanomethyl ether (0.088 g) in methylene chloride (3 ml) which had been cooled to 3°C. The mixture was stirred at ambient temperature for 2.5 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and a 0.1N aqueous sodium hydroxide solution. The organic phase was washed with brine, dried (MgSO,) and evaporated. The residue was purified by column chromatography using a 4:3 mixture of petroleum ether (b.p. 40-60°C) and ethyl acetate as eluent. There was thus obtained (E)-4'-{3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4- yljphenylsulphonyl}acetophenone oxime O-cyanomethyl ether (0.06 g, 63%), m.p. 55-57°C; NMR Spectrum: 1.22 (d, 3H), 1.5-1.75 (m, 3H) , 2.1 (m, IH) , 2.27 (s, 3H), 3.9-4.0 (m, 3H) , 4.84 (s, 2H) , 7.52 (m, IH), 7.70 (m, IH) , 7.81 (m, 2H), 7.84 (m, IH), 7.96 (m, 2H) , 8.10 (m, IH). Example 10 Using an analogous procedure to that described in Example 9, (E)-4'-{3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]phenylthio}- acetophenone oxime 0-methyl ether was oxidised to give (E)-4'-{3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]phenyl- sulphonyl}acetophenone oxime 0-methyl ether in 87% yield, m.p. 48-49°C; NMR Spectrum: 1.22 (d, 3H) , 1.5-1.75 (m, 3H) , 2.1 (m, IH) , 2.21 (s, 3H), 3.9-4.0 (m, 3H) , 4.0 (s, 3H) , 7.49 (m, IH) , 7.68 (m, IH), 7.77 ( , 2H), 7.83 (m, IH) , 7.93 (m, 2H), 8.10 (m, IH). Example 11 Pivaloyl chloride (0.027 ml) was added to a stirred mixture of (E)-4'-{3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]phenyl¬ thio}acetophenone oxime (0.07 g), pyridine (0.018 ml) and THF (2 ml). The mixture was stirred at ambient temperature for 2 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water to which a IN hydrochloric acid solution (1 drop) had been added. The organic phase was washed with water and with brine, dried (MgSO.) and evaporated. The residue was purified by column chromatography using a 20:7 mixture of petroleum ether (b.p. 40-60°C) and ethyl acetate as eluent. There was thus obtained 0-pivaloyl-(E)-4'-{3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]- phenylthio}acetophenone oxime (0.1 g, 83%). NMR Spectrum: 1.21 (d, 3H), 1.33 (s, 9H), 1.5-1.76 (m, 3H), 2.1 (m, IH), 2.36 (s, 3H), 3.9-4.0 (m, 3H) , 7.2-7.45 (m, 5H) , 7.58 (m, IH), 7.66 (m, 2H). Example 12 Using an analogous procedure to that described in Example 6, '-{3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]phenylsulphonyl}- acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-{3-[(2S,4R)-4-hydroxy-2-n.ethyltetrahydropyran-4-yl]phenyl¬ sulphonyl}acetophenone oxime in 85% yield; NMR Spectrum: 1.22 (d, 3H) , 1.5-1.75 (m, 3H) , 2.1 (m, IH), 2.26 (s, 3H), 3.9-4.0 (m, 3H) , 7.5 (m, IH) , 7.64 (m, IH) , 7.7 (m, IH) , 7.78 (m, 2H), 7.85 (m, IH) , 7.94 (m, 2H), 8.1 (broad s, IH) . The 4'-{3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]- phenylsulphonyl}acetophenone used as a starting material was obtained by oxidation of 4'-{3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]- phenylthio}acetophenone using an analogous procedure to that described in Example 9. The compound was obtained in 73% yield, m.p. 125-126°C. Example 13 Using an analogous procedure to that described in Example 11, (E)-4'-{3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]phenyl¬ sulphonyl}acetophenone oxime was reacted with pivaloyl chloride to give 0-pivaloyl-( E)-4'-{3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yll- phenylsulphonyl}acetophenone oxime in 80% yield; NMR Spectrum: 1.22 (d, 3H), 1.33 (s, 9H), 1.5-1.77 (m, 3H) , 2.1 (m, IH), 2.38 (s, 3H), 3.9-4.0 (m, 3H) , 7.52 (m, IH) , 7.69 (m, IH) , 7.82-8.0 (m, 5H) , 8.09 (m, IH) . Example 14 Using an analogous procedure to that described in Example 11, (E)-4'-{3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]phenyl¬ sulphonyl}acetophenone oxime was reacted with acetyl chloride to give 0-acetyl-(E)-4'-{3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]- phenylsulphonyl}acetophenone oxime in 50% yield, m.p. 131-132°C; NMR Spectrum: 1.22 (d, 3H) , 1.5-1.76 (m, 3H) , 2.1 (m, IH) , 2.26 (s, 3H), 2.39 (s, 3H), 3.9-4.0 (m, 3H), 7.5 (m, IH), 7.7 (m, IH) , 7.8-8.1 (m, 6H). Example 15 A mixture of 4'-{4-[ (2S,4R)-4-hydroxy-2-methyltetra- hydropyran-4-yl]thien-2-ylthio}acetophenone (0.73 g), hydroxylamine hydrochloride (0.16 g) and pyridine (10 ml) was stirred and heated to 35°C for 1 hour. The mixture was poured into water (20 ml) and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO,) and evaporated. The residue was purified by column chromatography using a 3:7 mixture of petroleum ether (b.p. 40-60°C) and ethyl acetate as eluent. There was thus obtained (E_)-4'-{4- [ (2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]thien-2-ylthio}- acetophenone oxime (0.64 g, 84%), m.p. 47-49°C; NMR Spectrum: 1.22 (d, 3H), 1.63-1.78 (m, 3H) , 2.1 (m, IH), 2.23 (s, 3H), 3.9-4.0 (m, 3H) , 7.2-7.5 ( , 4H), 7.52 (m, 2H) , 7.62 (m, IH) . The 4'-{4-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]- thien-2-ylthio}acetophenone used as a starting material was obtained as follows:- A solution of 1,2-dibromoethane (5 g) in diethyl ether (10 ml) was added to a stirred suspension of magnesium (3 g) in diethyl ether (10 ml) to initiate the formation of a Grignard reagent. A mixture of 1,2-dibromoethane (16.7 g) and 3-bromothiophene (4 g) in diethyl ether (30 ml) was added dropwise. The mixture was stirred and heated to reflux for 2 hours. A solution of (2S)-2-methyl- tetrahydropyran-4-one (2 g) in diethyl ether (5 ml) was added and the mixture was heated to reflux for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO,) and evaporated. The residue was purified by column chromatography using a 7:3 mixture of petroleum ether and ethyl acetate as eluent. There were thus obtained in turn (2S,4R)-4-hydroxy-2-methyl-4-(3- thienyl)tetrahydropyran (0.685 g, 18.5%) and the corresponding (2S,4S)-isomer (1 g, 32%). Using an analogous procedure to that described in Example 3, the (2S,4R)-isomer was reacted with methyl iodide to give (2S,4R)-4-methoxy-2-methyl-4-(3-thienyl)tetrahydropyran in 61% yield as an oil. n-Butyl-lithium (1.6M in hexane, 2.82 ml) was added dropwise to a stirred solution of diisopropylamine (0.64 ml) in THF (6.5 ml) which had been cooled to -78°C. The mixture was stirred at -60°C for 30 minutes. The mixture was recooled to -78°C and a solution of (2S,4R)-4-methoxy-2-methyl-4-(3-thienyl)tetrahydropyran (0.63 g) in THF (1.6 ml) was added dropwise. The mixture was allowed to warm to -15°C and was stirred for 3 hours. The mixture was recooled to -78°C and a solution of di-[4-(2-methyl-l,3-dioxolan-2-yl)phenyl] disulphide (1.15 g) in THF (18 ml) was added dropwise. The mixture was stirred at -78°C for 90 minutes and then allowed to warm gradually to ambient temperature. The mixture was partitioned between ethyl acetate and a cooled saturated aqueous ammonium chloride solution. The organic phase was dried (MgSO,) and evaporated. The residue was purified by column chromatography using a 41:9 mixture of petroleum ether (b.p. 40-60°C) and ethyl acetate as eluent. There was thus obtained 4'-{4-[ (2S,4R)-4- methoxy-2-methyltetrahydropyran-4-yl]thien-2-ylthio}acetophenone ethylene acetal as an oil (0.75 g, 62%). 2N Aqueous hydrochloric acid (2 drops) was added to a stirred solution of -a portion (0.5 g) of the ethylene acetal so obtained in acetone (5 ml) and the mixture was stirred at ambient temperature for 2 hours. The mixture was neutralised by the addition of sodium bicarbonate and evaporated. The residue was purified by column chromatography using a 7:3 mixture of petroleum ether (b.p. 40-60°C) and ethyl acetate as eluent. There was thus obtained 4'-{4-[(2S,4R)-4- methoxy-2-methyltetrahydropyran-4-yl]thien-2-ylthio}acetophenone as an oil (0.42 g, 94%). Concentrated sulphuric acid (35%, 0.2 ml) was added dropwise to a stirred solution of 4'-{4-[(2S,4R)-4-methoxy-2-methyltetrahydro- pyran-4-yl]thien-2-ylthio}acetophenone (1.5 g) in diethyl ether (30 ml) which had been cooled to 0°C. The mixture was allowed to warm to ambient temperature and was stirred for 3 hours. The mixture was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic phase was washed with water, dried (MgSO,) and evaporated. The residue was purified by column chromatography using initially a 7:3 mixture of petroleum ether (b.p. 40-60°C) and ethyl acetate and then a 3:2 mixture of those solvents as eluent. There was thus obtained 4'-{4-[ (2S,4R)-4-hydroxy-2-methyl- tetrahydropyran-4-yl]thien-2-ylthio}acetophenone as an oil (0.75 g, 52%). Example 16 Using an analogous procedure to that described in Example 8, (E)-4'-{4-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]thien-2- ylthio}acetophenone oxime was reacted with bromoacetonitrile to give (E)-4'-{4-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]thien-2- ylthio}acetophenone oxime O-cyanomethyl ether in 61% yield; NMR Spectrum: 1.22 (d, 3H) , 1.64-1.85 (m, 3H) , 2.08 (m, IH) , 2.22 (s, 3H), 3.87-4.0 (m, 3H), 4.81 (s, 2H), 7.27 (m, 2H), 7.32 (d, IH), 7.37 (d, IH), 7.56 (m, 2H) . Example 17 Using an analogous procedure to that described in Example 9, (E)-4'-{4-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]thien-2- ylthio}acetophenone oxime O-cyanomethyl ether was oxidised to give (E_)-4'-{4-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]thien-2- ylsulphonyl)acetophenone oxime O-cyanomethyl ether in 80% yield; NMR Spectrum: 1.20 (d, 3H), 1.55-1.8 (m, 3H), 2.0 (m, IH), 3.82-3.94 (m, 3H), 4.85 (s, 2H), 7.53 (d, IH) , 7.71 (d, IH), 7.82 (m, 2H) , 8.10 (m, 2H). Example 18 Using an analogous procedure to that described in Example 15, 4'-{4-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]thien-2- ylsulphonyl}acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-{4-[ (2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]- thien-2-ylsulphonyl}acetophenone oxime in 54% yield; NMR Spectrum: 1.20 (d, 3H), 1.6-1.8 (m, 3H), 2.0 (m, IH) , 2.28 (s, 3H) , 3.82-3.92 (m, 3H) , 7.50 (d, IH), 7.69 (d, IH) , 7.78 (m, 2H), 7.98 (m, 2H). The 4'-{4-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]- thien-2-ylsulphonyl}acetophenone used as a starting material was obtained as follows:- A solution of potassium peroxymonosulphate (1.23 g) in water (14 ml) was added dropwise to a stirred solution of 4'-{4-[(2S,4R)-4- methoxy-2-methyltetrahydropyran-4-yl]thien-2-ylthio}acetophenone (0.42 g) in methanol (10 ml) which had been cooled to 0 C C. The acidity of the solution was adjusted to pH5 by the addition of sodium acetate and the mixture was stirred and heated to 40°C for 4 hours. The mixture was evaporated and the residue was purified by column chromatography using a 1:1 mixture of petroleum ether (b.p. 40-60°C) and ethyl acetate as eluent. There was thus obtained 4'-{4-[(2S,4R)-4-methoxy-2-methyl- tetrahydropyran-4-yl]thien-2-ylsulphonyl}acetophenone (0.3 g, 67%), m.p. 114-115°C. The product so obtained was reacted with concentrated sulphuric acid using an analogous procedure to that described in the fifth paragraph of the portion of Example 15 which is concerned with the preparation of starting materials. There was thus obtained the required starting material in 54% yield. Example 19 The following illustrate representative pharmaceutical dosage forms containing the compound of formula I, or a pharmaceutically-acceptable salt thereof (hereafter compound X), for therapeutic or prophylactic use in humans: (a) Tablet I mg/tablet Compound X 100 Lactose Ph.Eur 182.75 Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25 Magnesium stearate 3.0 (b) Tablet II mg/tablet Compound X 50 Lactose Ph.Eur 223.75 Croscarmellose sodium 6.0 Maize starch 15.0 Polyvinylpyrrolidone (5% w/v paste) 2.25 Magnesium stearate 3.0 (c) Tablet III g/tablet Compound X 1.0 Lactose Ph.Eur 93.25 Croscarmellose sodium 4.0 Maize starch paste (5% w/v paste) 0.75 Magnesium stearate 1.0 (d) Capsule mg/capsule Compound X 10 Lactose Ph.Eur 488.5 Magnesium stearate 1.5 (e) Injection I (50 mg/ml) Compound X 5.0% w/v IM Sodium hydroxide solution 15.0% v/v 0.1M Hydrochloric acid "(to adjust pH to 7.6) Polyethylene glycol 400 4.5% w/v Water for injection to 100% (f) Injection II (10 mg/ml) Compound X 1.0% w/v Sodium phosphate BP 3.6% w/v 0.1M Sodium hydroxide solution 15.0% v/v Water for injection to 100% (g) Injection III (lmg/ml,buffered to pH6) Compound X 0.1% w/v Sodium phosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol 400 3.5% w/v Water for injection to 100% (h) Aerosol I mg/ml Compound X 10.0 Sorbitan trioleate 13.5 Trichlorofluoromethane 910.0 Dichlorodifluoro ethane 490.0 (i) Aerosol II mg/ml Compound X 0.2 Sorbitan trioleate 0.27 Trichlorofluoromethane 70.0 Dichlorodifluoromethane 280.0 Dichlorotetrafluoroethane 1094.0 (j) Aerosol III mg/ml Compound X 2.5 Sorbitan trioleate 3.38 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0 Dichlorotetrafluoroethane 191.6 (k) Aerosol IV mg/ml Compound X 2.5 Soya lecithin 2.7 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0 Dichlorotetrafluoroethane 191.6 Note The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate. The aerosol formulations (h)-(k) may be used in conjunction with standard, metered dose aerosol dispensers, and the suspending agents sorbitan trioleate and soya lecithin may be replaced by an alternative suspending agent such as sorbitan monooleate, sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleic acid.

Claims: 4/17054 46 CLAIMS 1. An oxime derivative of the formula I OR 1 R 5 0-N=C(R 4 ) -Ar 1 -A 1 -X 1 -Ar 2 -C-R 2 I I R 3 4 wherein R is hydrogen, carboxy, carbamoyl, amino, cyano, trifluoromethyl, (1-4C)alkylamino, di-(l-4C)alkylamino, (l-4C)alkyl, (2-5C)alkanoyl, (l-4C)alkoxycarbonyl, N-(l-4C)alkylcarbamoyl, N,N-di-(l-4C)alkylcarbamoyl, (l-4C)alkylthio, (l-4C)alkylsulphinyl, (l-4C)alkylsulphonyl, hydroxy-(1-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, (l-4C)alkylthio-(l-4C)alkyl, phenyl or phenyl-(l-4C)alkyl and wherein each phenyl group may optionally bear one or two substituents selected from hydroxy, amino, halogeno, cyano, trifluoromethyl, (1-4C)alkyl, (l-4C)alkoxy, (l-4C)alkylamino, di-(l-4C)alkylamino, (1-4C)alkylthio, (l-4C)alkylsulphinyl and (l-4C)alkylsulphonyl; R 5 is hydrogen, (l-4C)alkyl, (3-4C)alkenyl, (3-4C)alkynyl, (2-5C)alkanoyl, halogeno-(2-4C)alkyl, hydroxy-(2-4C)alkyl, (l-4C)alkoxy-(2-4C)alkyl, carbamoyl, N-(l-4C)alkylcarbamoyl, N,N-di-(l-4C)alkylcarbamoyl, cyano-(1-4C)alkyl, carboxy-(1-4C) lkyl, (l-4C)alkoxycarbonyl-(l-4C)alkyl, (2-5C)alkanoyl-(l-4C)alkyl, phenyl-(1-4C)alkyl or heteroaryl-(1-4C)alkyl and wherein each phenyl or heteroaryl group may optionally bear one or two substituents selected from halogeno, cyano, trifluoromethyl, carboxy, (l-4C)alkyl, (l-4C)alkoxy and (l-4C)alkoxycarbonyl; Ar is phenylene or a heteroaryl diradical which may optionally bear one or two substituents selected from halogeno, cyano, trifluoromethyl, hydroxy, amino, (l-4C)alkyl, (l-4C)alkoxy, phenyl-(l-4C)alkoxy, (1-4C)alkylamino and di-(l-4C)alkylamino; 4 1 4 or R is linked to Ar ortho to the -N=C(R )- group and defines an ethylene, propylene, 1-methylpropylene or vinylene group, a group of the formula -CH=CH-X 3 - 3 wherein X is oxy or thio, or a group of the formula -(CH„) -X 3 - 2 ; n 3 wherein n is 1 or 2, X is oxy, thio, sulphinyl, sulphonyl, imino or (l-4C)alkylimino, and one of the -CH 2 ~ groups may optionally be replaced by a -CH(Me)- or -C(Me) - group; 1 1 1 A is a direct link to X , or A is (l-4C)alkylene; X is oxy, thio, sulphinyl or sulphonyl; 2 Ar is phenylene, pyridinediyl, pyrimidinediyl, thiophenediyl, furandiyl, thiazolediyl, oxazolediyl, thiadiazolediyl or oxadiazolediyl which may optionally bear one or two substituents selected from halogeno, cyano, trifluoromethyl, hydroxy, amino, (1-4C)alkyl, (l-4C)alkoxy, (1-4C)alkylamino and di-(l-4C)alkylamino; R is hydrogen, (2-5C)alkanoyl or benzoyl, and wherein said benzoyl group may optionally bear one or two substituents selected from halogeno, (1-4C)alkyl and (l-4C)alkoxy; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 ring having 5 or 6 ring atoms, wherein each of A and A is 2 independently (l-3C)alkylene and X is oxy, thio, sulphinyl, sulphonyl or imino, and which ring may optionally bear one or two substituents selected from hydroxy, (1-4C)alkyl and (l-4C)alkoxy; or a pharmaceutically-acceptable salt thereof. 2. An oxime derivative of the formula I as claimed in claim 1 4 wherein R is hydrogen, cyano, trifluoromethyl, dimethylamino, methyl, ethyl, propyl, isopropyl, acetyl, methoxycarbonyl, ethoxycarbonyl, methylthio or phenyl; R is hydrogen, methyl, ethyl, propyl, isopropyl, allyl, prop-2-ynyl, acetyl, propionyl, butyryl, pivaloyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, cyanomethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl or 2-, 3- or 4-pyridylmethyl; Ar is 1,4-phenylene which may optionally bear one substituent selected from fluoro, chloro, hydroxy, methyl, methoxy and benzyloxy; or Ar is 1,4-phenylene and R is linked to Ar ortho to the -N=C(R )• group and defines an ethylene or vinylene group, or a group of the formula -CH 2 CH 2 0-; A is a direct link to X and X is thio or sulphonyl, or A is methylene and X is oxy; 2 Ar is 1,3-phenylene which may optionally bear one or two fluoro 2 substituents, or Ar is 3,5-pyridinediyl, 2-amino-4,6-pyrimidinediyl, 2,4- or 2,5-thiophenediyl or 2,4- or 2,5-thiazolediyl; R is hydrogen; 2 3 2 2 3 and R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 ring having 5 or 6 ring atoms, wherein A is methylene or ethylene, A 2 is ethylene and X is oxy, and which ring may optionally bear one or two substituents selected from methyl and ethyl; or a pharmaceutically-acceptable salt thereof. 3. An oxime derivative of the formula I as claimed in claim 1 4 wherein R is methyl, ethyl, isopropyl, hydroxymethyl or methoxymethyl; R is hydrogen, methyl, allyl, prop-2-ynyl, acetyl, pivaloyl, 2-hydroxyethyl, cyanomethyl, acetonyl, 3-pyridylmethyl or 4-pyridylmethyl; Ar is 1,4-phenylene or 2,5-pyridinediyl (with the X group in the 2-position) ; A is a direct link to X and X is thio or sulphonyl; 2 Ar is 1,3-phenylene, 5-fluoro-l,3-phenylene, 2,4-thiophenediyl (with the X group in the 2-position) , 2,4-thiazolediyl (with the X group in the 2-position) or 2,5-thiazolediyl (with the X group in the 2-position) ; R is hydrogen; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 ring having 5 or 6 ring atoms, wherein A is methylene or ethylene, A 2 is ethylene and X is oxy, and which ring may optionally bear a methyl 2 substituent alpha to X ; or a pharmaceutically-acceptable salt thereof. 4. An oxime derivative of the formula I as claimed in claim 1 wherein R iiss hhyyddrrooggeenn,, mmeetthhyyll,, aacceeityl, pivaloyl, cyanomethyl, 3- •ppyyrriiddyyllmmeetthhyyll oorr 44--ppyyrriiddyyllmmeetthhyyll;; 1 4 AArr iiss 11,,44--pphheennyylleennee aanndd RR iiss lliinnkk*ed to Ar ortho to the -N=C(R ) group and defines an ethylene group, or a group of the formula -CH 2 CH 2 0-; A is a direct link to X and X is thio, or A is methylene and X is oxy; 2 Ar is 1,3-phenylene, 5-fluoro-l,3-phenylene, 2-amino-4,6-pyrimidinediyl, 2,4-thiophenediyl (with the X group in the 2-position) or 2,5-thiazolediyl (with the X group in the 2-position); R is hydrogen; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 ring having 5 or 6 atoms, wherein A is methylene or ethylene, A is 2 ethylene and X is oxy, and which ring may optionally bear a methyl 2 substituent alpha to X ; or a pharmaceutically-acceptable salt thereof. 5. An oxime derivative of the formula I as claimed in claim 1 4 wherein R is methyl; R is hydrogen, methyl, prop-2-ynyl, acetyl, pivaloyl or cyanomethyl; Ar is 1,4-phenylene; A is a direct link to X and X is thio or sulphonyl; 2 Ar is 1,3-phenylene, 5-fluoro-l,3-phenylene, 2,5-difluoro-l,3-phenylene or 2,4-thiophenediyl (with the X group in the 2-position) ; R is hydrogen; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which ? 3 together with the carbon atom to which A" and A are attached define a 2 3 2 ring having 6 ring atoms, wherein each of A and A is ethylene and X is oxy, and which ring may optionally bear a methyl substituent alpha to X ; or a pharmaceutically-acceptable salt thereof. 6. An oxime derivative of the formula I as claimed in claim 1 being:- (E)-4'-{5-fluoro-3-[ (2S,4R)-4-hydroxy-2-methyltetrahydropyran-4- yl]phenylthio}acetophenone oxime; or a pharmaceutically-acceptable salt thereof. 7. An oxime derivative of the formula I as claimed in claim 1 selected from:- (E)-4'-{5-fluoro-3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]- phenylsulphonyl}acetophenone oxime, (E)-4'-{5-fluoro-3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]- phenylsulpho yl}acetophenone oxime O-cyanomethyl ether, (E)-4'-{3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]phenylthio}- acetophenone oxime 0-methyl ether, {__)-4'-{3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]phenyl¬ sulphonyl}acetophenone oxime O-cyanomethyl ether, (E)-4'-{3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]phenyl¬ sulphonyl}acetophenone oxime 0-methyl ether, (E)-4'-{4-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]thien-2- ylthio}acetophenone oxime, (E)-4'-{4-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]thien-2- ylthio}acetophenone oxime O-cyanomethyl ether, (E_)-4'-{4-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]thien-2- ylsulphonyl}acetophenone oxime O-cyanomethyl ether and (E)-4'-{4-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]thien-2- ylsulphonyl}acetophenone oxime; or a pharmaceutically-acceptable salt thereof. 8. A process for the preparation of an oxime derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 7 which comprises:- (a) the reaction of a compound of the formula II OR 1 0=C(R 4 )-Ar 1 -A 1 -X 1 -Ar 2 -C-R 2 II R " with a hydroxylamine of the formula R 0-NH«; (b) for the production of those compounds of the formula I wwhheerreeiinn RR iiss ((l1--44CC))aallkkyyl. 1 or substituted-alkyl, the alkylation of an oxime of the formula III OR 1 1 2 H0-N=C(R 4 )-Ar 1 - ■ A -X -Ar -C- R' III with an alkylating agent of the formula R -Z, wherein Z is a displaceable group; (c) for the production of those compounds of the formula I wherein R is (2-5C)alkanoyl, carbamoyl, N-(l-4C)alkylcarbamoyl or N,N-di-(l-4C)alkylcarbamoyl, the acylation of an oxime of the formula III OR 1 H0-N=C(R 4 )-Ar 1 -A 1 -X 1 -Ar 2 -C-R 2 III with an acylating agent of the formula R -Z, wherein Z is a displaceable group; (d) for the production of those compounds of the formula I wherein R is cyano or (2-5C)alkanoyl, the reaction of a compound of the formula IV OR 1 I R 4 -CH 2 -Ar 1 -A 1 -X 1 -Ar 2 -C-R 2 IV I R 3 with an alkylnitrite; (e) for the production of those compounds of the formula I 4 wherein R is amino, (1-4C)alkylamino, di-(l-4C)alkylamino or (l-4C)alkylthio, the alkylation of ammonia, a (l-4C)alkylamine, a di-(l-4C)alkylamine or a (l-4C)alkanethiol with an alkylating agent of the formula V OR 1 I 5 1 1 1 2 2 R J 0-N=C(Z)-Ar -A -X -Ar -C-R V I R 3 wherein Z is a displaceable group; (f) the coupling of a compound of the formula VI R 5 0-N=C(R )-Ar 1 -A 1 -X 1 -Z VI wherein Z is a displaceable group, or alternatively, when X is a thio group, Z may be a group of the formula R 5 0-N=C(R )-Ar 1 -A 1 -X 1 - with an organometallic reagent of the formula VII OR 2 2 M-Ar -C-R VII wherein M is an alkali metal or alkaline earth metal or M represents the magnesium halide portion of a conventional Grignard reagent; (g) for the production of those compounds of the formula I 1 2 3 wherein X is a sulphinyl or sulphonyl group, or wherein R and R 2 2 3 2 together form a group of the formula -A -X -A - and X is a sulphinyl or sulphonyl group, the oxidation of a compound of the formula I 1 2 3 wherein X is a thio group, or wherein R and R together form a group 2 2 3 2 of the formula -A -X -A - and X is a thio group; or (h) for the production of those compounds of the formula I wherein R is a carboxy-(1-4C)alkyl group, the hydrolysis of a compound of the formula I wherein R is a (l-4C)alkoxycarbonyl-(l-4C)alkyl group; and when a pharmaceutically-acceptable salt of a compound of the formula I is required, it may be obtained by reaction of said compound with a suitable acid or base using a conventional procedure; and when an optically active form of a compound of the formula I is required, it may be obtained by carrying out one of the aforesaid procedures using an optically active starting material, or by resolution of a racemic form of said compound using a conventional procedure. 9. A pharmaceutical composition which comprises an oxime derivative of the formula I, or a pharmaceutically- acceptable salt thereof, as claimed in any one of claims 1 to 7 in association with a pharmaceutically-acceptable diluent or carrier. 10. The use of an oxime derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 7 in the production of a new medicament for use in a leukotriene mediated disease or medical condition.

Inventors: LARGE MICHAEL STEWART, LARGE, MICHAEL, STEWART
Applicants: LARGE MICHAEL STEWART, ZENECA LTD, ZENECA PHARMA SA, LARGE, MICHAEL, STEWART, ZENECA LIMITED, ZENECA-PHARMA S.A.
Application year: 1994
Main classification: C07D309
IPC codes: A61K31, A61P29, A61P37, C07D309, C07D409